TY - JOUR T1 - Proteasome subunit <em>PSMC3</em> variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress JF - bioRxiv DO - 10.1101/836015 SP - 836015 AU - Ariane Kröll-Hermi AU - Frédéric Ebstein AU - Corinne Stoetzel AU - Véronique Geoffroy AU - Elise Schaefer AU - Sophie Scheidecker AU - Séverine Bär AU - Masanari Takamiya AU - Koichi Kawakami AU - Barbara A. Zieba AU - Fouzia Studer AU - Valerie Pelletier AU - Claude Speeg-Schatz AU - Vincent Laugel AU - Dan Lipsker AU - Florian Sandron AU - Steven McGinn AU - Anne Boland AU - Jean-François Deleuze AU - Lauriane Kuhn AU - Johana Chicher AU - Philippe Hammann AU - Sylvie Friant AU - Christelle Etard AU - Elke Krüger AU - Jean Muller AU - Uwe Strähle AU - Hélène Dollfus Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/17/836015.abstract N2 - Whole-genome sequencing was performed on patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome. A unique deep intronic homozygous variant in the PSMC3 gene (c.1127+337A&gt;G, p.Ser376Argfs15*), encoding the 26S proteasome ATPase ring subunit 5 (Rpt5) was identified leading to the transcription of a cryptic exon. Patient’s fibroblasts exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient’s fibroblasts. Upon chemical proteasome inhibition this pathway is however impaired. These cells were unable to compensate for proteotoxic stress although a higher proteasome content. Two different zebrafish studies led to inner ear development anomalies as well as cataracts. PSMC3 proteasome subunit dysfunction leads to various neurological manifestations, early onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear, lens and central nervous system development. ER -